The syngeneic or autologous mixed lymphocyte reaction (SMLR) has been defined as a T cell proliferative response to in vitro stimulation with syngeneic or autologous non-T cells, bearing Ia antigens. Although the SMLR has been well characterized, the nature and functional significance of the responding T cells in vivo has not been resolved. To address these issues we have developed a series of T cell clones which recognize self-Ia in the absence of foreign antigens. These cells serve as helper T cells in the proliferation of antigen reactive T cells and alloreactive cytotoxic T cells and trigger the proliferation and differentiation of resting B cells, but in preliminary experiments do not appear to contain antigen reactive T cells. Based on these observations we wish to : 1) determine if autoreactive T cells which respond in the SMLR are antigen responsive T cells; 2) identify a T cell marker specific for autoreactive but not alloreactive T cells and to prepare monoclonal antibodies for the characterization of the T cell receptor which recognizes self-Ia; 3) analyze the immunoregulatory role of autoreactive T cells in vitro and determine the effects of in vivo depletion of SMLR reactive T cells on the immune response; and 4) analyze the basis of the response of normal Lyl+2-/L3T4+ T cells to autoreactive T cells. Experiments have been designed to determine if low affinity T cell receptor interactions with Ia are essential in the triggering of T cells and to analyze the relationship of autoreactive T cell clones to cloned antigen-specific T cell lines. These experiments will utilize a series of well characterized autoreactive T cell clones for preparation of T cell hybridomas and monoclonal antibodies to the T cell receptor for Ia with the ultimate goal of characterizing the T cell receptor for self-Ia and its relationship to the antigen-specific T cell receptor. Our recent observation that normal Lyl+2-/L3T4+ T cells respond specifically to autoreactive T cells suggests that there may be an autoregulatory network and preliminary experiments to investigate the specificity and basis of recognition of this T-T interaction are outlined. These experiments should shed light on the role of autoreactive T cells on regulation of the immune response and may provide insights as to how these cells participate in autoimmunity and neoplasia.